An FDA advisory committee on Thursday voted unanimously against recommending approval of serelaxin injection for patients with acute heart failure.

An FDA advisory committee on Thursday voted unanimously against recommending approval of serelaxin injection for patients with acute heart failure.

All 11 members of the agency's Cardiovascular and Renal Drugs Advisory Committee failed to see enough evidence of the drug's benefit to support approval, although several expressed optimism about serelaxin's prospects moving forward into further studies.

For serelaxin believers the good news was a general agreement that the drug did not worsen heart failure.

"I think it's clear the drug does have an effect on worsening heart failure but given the limitations of how that was not rigorously defined, we don't know how much of the effect is on minor heart failure changes versus major," said committee chair A. Michael Lincoff, MD, of the Cleveland Clinic.

"We need better data on understanding the magnitude of benefit in a rigorous fashion," he added, saying that the data presented were not strong enough to support approval based on a single trial.

"We've not had a positive drug approval for heart failure in some time," he told MedPage Today. "Given the totality of available data, a negative FDA response today will further stymie new drug discovery. With the importance of heart failure, now is not the time to impede discovery. We should go forward, not backwards."

Novartis, which is developing serelaxin, was seeking approval of the drug to improve the symptoms of acute heart failure through a reduction in the rate of worsening of heart failure.

But FDA briefing documents released before the meeting indicated that that would be a tough sell. The agency reviewers did not have any major safety concerns but recommended against approval "because there is insufficient evidence to support the proposed indication."

They questioned the broader indication of improving symptoms in general because the two primary endpoints of the supporting RELAX-AHF trial dealt only with dyspnea. Only one of the two endpoints needed to achieve statistical significance for the trial to be considered a success, and that was achieved with the change in dyspnea from baseline through 5 days using the area under the curve of a visual analog scale.

But heart failure trials look for small wins, which meant RELAX-AHF was rated a success by many true believers. Neither FDA staff nor the panel members belong to the true believer camp, and, as a result, they pointed out that the P-value associated with the difference on the positive outcome was not strong enough to support approval based on a single trial.

In addition, there was extensive discussion during the meeting about how the dyspnea values were imputed as part of that endpoint in relation to worsening heart failure events.

Even though the endpoint indicated an advantage for serelaxin, there was confusion about whether that was indicative of an improvement in dyspnea or in worsening heart failure, particularly because the other primary endpoint involving patient-reported dyspnea on a Likert scale did not show a difference between the two groups.

"The statistical success of the trial was driven entirely by the imputation rule for worsening heart failure events with essentially no difference in the degree of subject-reported dyspnea," according to the briefing documents.

Some panelists were intrigued by the other apparent benefits of serelaxin.

"I think there's real potential for this drug to improve worsening of heart failure, potentially shorten hospital stay, potentially favorably improve both renal and troponin biomarkers," said Philip Sager, MD, of Stanford University, adding, however, that he doesn't think any of the potential benefits go beyond hypothesis-generating at this point.

"I hope that this disappointing vote and meeting today won't preclude the sponsor from continuing to develop the drug," he said.

There was also some discussion about the reduction in mortality seen with serelaxin at 6 months, but there was a general skepticism about the finding without confirmation in future studies.

In anticipation of the need for confirmation of the findings, Novartis initiated the RELAX-AHA-2 trial -- which is expected to be five times larger than the first trial -- in September.

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